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Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.

Authors
  • Avanzi, Mauro P1
  • Yeku, Oladapo2
  • Li, Xinghuo3
  • Wijewarnasuriya, Dinali P3
  • van Leeuwen, Dayenne G1
  • Cheung, Kenneth1
  • Park, Hyebin1
  • Purdon, Terence J1
  • Daniyan, Anthony F1
  • Spitzer, Matthew H4
  • Brentjens, Renier J5
  • 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected]
  • 3 Weill Cornell School of Medicine, New York, NY, USA.
  • 4 Department of Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
May 15, 2018
Volume
23
Issue
7
Pages
2130–2141
Identifiers
DOI: 10.1016/j.celrep.2018.04.051
PMID: 29768210
Source
Medline
Keywords
License
Unknown

Abstract

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy.

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